Zhang Min, Shi Jun, Zhou Jun, Song Lei, Ding Jingjing, Deng Hui Ping, Weng Li, Zhu Yiqian, Xu Zhongqing
Division of Cardiology, Hongqiao International Institute of Medicine, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, 200336 Shanghai, China.
Shanghai Institute of Pollution Control and Ecological Security, Key Laboratory of Yangtze River Water Environment Ministry of Education, College of Environmental Science and Engineering, Tongji University, Shanghai, China.
Ecotoxicol Environ Saf. 2023 Jun 22;262:115174. doi: 10.1016/j.ecoenv.2023.115174.
Owing to their potential adverse health effects, global contamination by microplastics (MPs) has attracted increased scientific and societal concerns. However, in vivo studies on MP toxicity, along with its effects and underlying mechanisms, remain limited. We recently found that non-coding RNA (ncRNAs) contribute to MP-mediated vascular toxicity. Moreover, previous studies have identified N6-methyladenosine (m6A) modifications in ncRNAs as influencing factors in cardiovascular disease. However, whether and how m6A modifications in ncRNAs are affected by MP-induced cardiotoxicity remain unknown. Herein, we profiled differentially expressed ncRNAs and their related m6A modification profiles in MP-exposed myocardial tissue using RNA sequencing (RNA-seq) and methylated RNA immunoprecipitation sequencing (MeRIP-seq). First, we observed that MPs accumulated in different organs and upregulated apoptosis in the heart, liver, spleen, and kidney cells. Furthermore, total m6A and METTL3 levels increased in the myocardium after exposure to MPs. RNA-seq results revealed that 392 lncRNAs and 302 circRNAs were differentially expressed in MP-treated mouse myocardium compared to the control group. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses showed that these altered lncRNAs and circRNAs were closely associated with endocytosis, cellular senescence, and cell cycle signaling pathways, which may cause cardiotoxicity. Furthermore, MeRIP-seq data showed different distributions and abundances of m6A modifications in lncRNAs and circRNAs. Additionally, we identified differentially m6A methylated lncRNAs and circRNAs through conjoint analysis of the two high-throughput sequencing datasets and found that both m6A modifications and the expression of circ-Arfgef2 and lncG3bp2 were upregulated after exposure to MPs. This suggests that MP-induced m6A modifications in ncRNAs are involved in cardiotoxicity. Our findings contribute to a better understanding of MP-induced cardiotoxicity and new molecular targets for treating cardiac injury.
由于微塑料（MPs）对健康具有潜在的不利影响，其在全球范围内的污染已引起科学界和社会越来越多的关注。然而，关于MPs毒性的体内研究及其影响和潜在机制仍然有限。我们最近发现非编码RNA（ncRNAs）参与了MP介导的血管毒性。此外，先前的研究已确定ncRNAs中的N6-甲基腺苷（m6A）修饰是心血管疾病的影响因素。然而，ncRNAs中的m6A修饰是否以及如何受到MP诱导的心脏毒性影响仍不清楚。在此，我们使用RNA测序（RNA-seq）和甲基化RNA免疫沉淀测序（MeRIP-seq）对暴露于MPs的心肌组织中差异表达的ncRNAs及其相关的m6A修饰谱进行了分析。首先，我们观察到MPs在不同器官中积累，并上调了心脏、肝脏、脾脏和肾脏细胞中的细胞凋亡。此外，暴露于MPs后心肌中的总m6A和METTL3水平升高。RNA-seq结果显示，与对照组相比，在MP处理的小鼠心肌中392个长链非编码RNA（lncRNAs）和302个环状RNA（circRNAs）差异表达。基因本体论和京都基因与基因组百科全书富集分析表明，这些改变的lncRNAs和circRNAs与内吞作用、细胞衰老和细胞周期信号通路密切相关，这可能导致心脏毒性。此外，MeRIP-seq数据显示lncRNAs和circRNAs中m6A修饰的分布和丰度不同。此外，我们通过对两个高通量测序数据集的联合分析鉴定了差异m6A甲基化的lncRNAs和circRNAs，并发现暴露于MPs后m6A修饰以及circ-Arfgef2和lncG3bp2的表达均上调。这表明MP诱导的ncRNAs中的m6A修饰参与了心脏毒性。我们的研究结果有助于更好地理解MP诱导的心脏毒性以及治疗心脏损伤的新分子靶点。
